Chiral compounds, their synthesis and use as a support

ABSTRACT

The invention relates to a method which comprises synthesising bifunctional compounds then chiral compounds from the bifunctional compounds, also to synthesising supports comprising these chiral compounds, and the use of these supports for preparing or separating enantiomers, or for asymmetric synthesis. The invention also relates to bifunctional compounds, their use as a source of functionalised polymers, and to the chiral compounds, also to the use of these chiral compounds in a chiral support in the form of a three-dimensional network or for separating or preparing enantiomers, principally for analytical or preparative chromatography, and in a support for the production of chiral molecules by asymmetric synthesis.

FIELD OF THE INVENTION

The invention relates to a method which comprises synthesisingbifunctional compounds then chiral compounds from the bifunctionalcompounds, also to synthesising supports comprising these chiralcompounds, normally in the form of a cross-linked three-dimensionalchiral network and generally with a modifiable degree of cross-linkingdepending on the desired degree of swelling, and the use of thesesupports for preparing and separating enantiomers, or for asymmetricsynthesis. The invention also relates to bifunctional compounds, theiruse as a source of functionalised polymers, and to the chiral compounds,also to the use of these chiral compounds in a chiral support forseparating and preparing enantiomers, principally for analytical orpreparative chromatography, and for asymmetric synthesis.

BACKGROUND OF THE INVENTION

Enantiomer separation is a field which has been expanding for abouttwenty years both on the preparative and on the analytical levels. Thisis particularly true in the pharmaceutical field, where the law requiresthe separate study of optical isomers of any chiral component of amedication composition. Substituted polysaccharides have been thesubject of a number of studies, and celluloses physically deposited on asilica gel support are commercially available. Such compounds have thedisadvantage, however, of usually being soluble in polar organicsolvents, which drastically limits their applications.

Recent solutions to the problem of solubility have been found by formingcovalent bonds between the substituted polysaccharide and the support.Kimata et al. have published their results (“Analytical methods andinstrumentation”, vol. 1, 23-29 (1993)) on a stationary chiral phasebased on -tris-2,3,6(4-vinylbenzoate) cellulose deposited on silica gel,then polymerised on the support.

Chromatographic data obtained with two racemic test mixtures were asfollows:

Deposited and polymerised Deposited support support Stilbene1-(1-naphthyl) Stilbene 1-(1-naphthyl oxide ethanol) oxide ethanol) k'11.08 2.15 1.04 1.47 k'2 1.66 2.84 1.44 1.80 α 1.54 1.32 1.39 1.22 R_(S)3.63 2.34 3.82 1.44

where:

k′1 and k′2 are partition ratios, i.e., if i=1 or 2,$k_{i}^{\prime} = \frac{t_{Ri} - t_{0}}{t_{o}}$

where t_(Ri) is the retention time of compound i;

and t₀ is the non-retained solute transit time;

α is the relative retention ratio:$\alpha = {\frac{t_{R2} - t_{0}}{t_{R1} - t_{0}} = \frac{k^{\prime}2}{k^{\prime}1}}$

R_(S) is the peak resolution:$R_{S} = {\frac{1}{4}\left( \frac{\alpha - 1}{\alpha} \right)\left( \frac{k^{\prime}2}{1 + {k^{\prime}2}} \right)(N)^{\frac{1}{2}}}$

where N is the plate number$N = {a\quad \left( \frac{t_{R}}{\omega} \right)^{2}}$

where ω is the peak width at a given ordinate, related to the square ofthe standard deviation or variance σ² by the relationship ω²=aσ², giving$N = {{16\quad \left( \frac{t_{R}}{\omega} \right)^{2}} = {5.54\left( \frac{t_{R}}{\sigma} \right)^{2}}}$

A systematic reduction in the relative retention ratios obtained can beseen between the deposited support and the deposited and polymerisedsupport: 10% less on the trans-stilbene oxide (α varies between 1.54 and1.39) and 25% less for the 1-(1-naphthyl)ethanol.

This phenomenon can be explained by partial solubility of thepolymerised support due to incomplete polymerisation because of weakreactivity of the vinyl benzoate group under the reaction conditionsused.

Kimata et al. did not describe any examples of separation in a purepolar solvent.

Okamoto et al. (in European patent EP-B-0 155 637) described polymerswhich are chemically bonded to a silica gel. In particular, theydescribed grafting tris-2,3,6-phenylcarbamate cellulose onto silica gelvia a tritylated intermediate, then forming a covalent bond between thesilica gel and the partially derived polysaccharide carbamate, by theaction of a diisocyanate.

The results of elemental analyses carried out during the differentstages of synthesis were as follows (EP-B-0 155 637, page 8 to page 9,line 33).

C% H% N% 1. Trityl cellulose deposited on silica 15.40  1.23 0.09 2.Detritylated cellulose deposited on silica 3.61 0.60 — 3. Cellulosebonded to silica by toluene-2,4- — — — diisocyanate 4. Cellulose phenylcarbamate bonded to 3.23 0.27 0.45 silica and washed with THF/chloroform

The drop in the degree of grafting between the cellulose deposited onsilica (2) and cellulose phenylcarbamate bonded to silica (4) isimportant knowing that the degree of (4) calculated after (2) is of theorder of 14% of carbon. The loss of hydrocarbon moieties can thus beestimated to be 80% from formation of the covalent bond between thecellulose and the silica by the diisocyanate arm, followed by derivativeformation by reacting the OH groups with phenyl isocyanate and finalwashing with chloroform.

No example of separation in polar solvents was given for the supportobtained.

Okamoto et al (Japanese patent JP 06-206-893) have described anoligosaccharide chemically bonded to silica gel by means of an iminefunction reduced to an amine. Amylose is then chemicoenzymaticallyregenerated from this oligosaccharide. The available hydroxyl functionsare then reacted with carbamate functions to form derivatives. Noexample of separation in a polar solvent was given.

It is important to use a large column excess for preparativeapplications. The possibility of using 100% of chiral material in theform of pure polymer beads of substituted polysaccharides instead ofphysically depositing them on a support has proved effective inincreasing mass yields in preparative chiral chromatographic processes.Thus patents EP-B-0 348 352, EP-B-0 316 270 and International patentapplication WO 96/27639 relate to the production of cellulose beads forseparating optical isomers.

However, pure polymer beads are soluble in polar solvents such ashalogenated solvents—tetrahydrofuran, dioxane, etc. It is thusimpossible to use these solvents either pure or in mixtures with highproportions of these solvents, to carry out isomer separation.

In order to overcome this disadvantage, Francotte et al. recommendedirradiation polymerisation of polysaccharide derivatives. (WO 96/27615).

However, the degree of polymerisation appears to be difficult to controlin such a process. No example of separation in a pure polar solvent isgiven.

Minguillon et al. described the synthesis of cellulose carbamates withpartial derivatives formed by reaction with an undecenoyl chloride.However, the structure of the support was not explained (J. ofChromatog. A 728 (1996), 407-414 and 415-422).

Lange (U.S. Pat. No. 5,274,167) described the polymerisation ofoptically active methacrylic acid derivatives, but the structure of thesupport was not explained. No example of separation in a pure polarsolvent was given.

The present invention concerns the preparation of novel chiral compoundsand their use in preparing or separating enantiomers, in particular on asupport or in polymer beads.

SUMMARY OF THE INVENTION

The chiral supports are obtained in the form of pure polymer beads ofthe chiral compound which is normally polymerised and cross-linked,preferably into a three-dimensional glycosidic network or obtained inthe form of a chiral compound attached to a support via a covalent bond,then polymerised and cross-linked, preferably into a three-dimensionalglycosidic network.

The chiral supports of the invention have remarkable stability in polarsolvents such as TIF (tetrahydrofuran), chloroform, methylene chloride,acetonitrile, toluene, acetone or ethyl acetate.

For the first time, separation of a racemic molecule on a support basedon a polysaccharide has been carried out in pure chloroform (seeExamples IA, IB, IC and ID).

This exceptional stability towards polar solvents of the novel chiralsupports is associated with the extremely fast mass transfer kineticsbetween the solutes and the three-dimensional glycosidic network. Againfor the first time, separations have been carried out in the normal orinverse mode using an elution gradient on stationary chiral phases (seeExamples IIA and IIB).

Further, we have noticed that the degree of cross-linking of the chiralsupports has an influence on the swelling capacity of the supports.Since the swelling capacity is variable, there are difficulties in usingit for analytical or preparative purposes in chromatographic processes:variable support volume, and the creation of large pressure drops duringswelling can result in columns which are of insufficient size explodingor percolation becoming impossible for those which resist highpressures; also, during shrinking, dead volumes are seen to form whichare incompatible with their current use.

The possibility of modifying the number and nature of the bifunctionalcompounds ensuring polymerisation and cross-linking per chiral unit hasthe advantage of enabling the degree of cross-linking and thus the finalperformance of the chiral support to be modified and in particular theswelling capacity in polar solvents can be controlled.

Further, we have noticed that the use of polar solvents mixed with otheralkane/alcohol type solvents can in some cases reverse the elution orderof enantiomers of compounds of biological importance (see Example III).When analysing the enantiomeric purity of chiral molecules, the gain insensitivity is thus significant. The compound which is eluted first isalways that with a higher number of theoretical plates than the second.

For the same reasons, the first enantiomer eluted in a preparativechiral chromatographic process is always the most pure and the mostconcentrated. There is thus a major interest in analytical andpreparative chiral chromatography is being able to control the order ofenantiomer exit.

The three-dimensional glycosidic network of novel chiral supports thusoffers this possibility through “matrix” effects, swelling to a greateror lesser extent depending on the degree of cross-linking of the supportand the nature of the polar solvent used. Depending on the spatialdisposition of the same functional constituents of each enantiomer, thematrix favours elution of one or other of the enantiomers by means of avariable three-dimensional structure.

The bifunctionality can bond chiral units, preferably glycosidic, viaone or more covalent bonds to constitute a polymerised and cross-linkedthree-dimensional network and thus the degree of cross-linking dependson:

the number of —OH, —NH₂, —NHR or SH functions in the chiral unit whichhave reacted or react with compounds:

[R—CH═CH—X—O]_(n)Ar—Q

[(R₁, R₂, R₃)Si—CH(R)—CH₂—X—O]_(n)Ar—Q

the number n of these same formulae

where R, X, n, Ar, R₁, R₂, and R₃ are defined below.

The —OH, —NH₂ or SH functions are generally and preferably partiallyreacted to form derivatives in the case where polar solvents are to beused and to benefit from the “matrix” effects relating thereto. Thedegree of cross-linking of the network, preferably a three-dimensionalchiral glycosidic network, is maximal and the swelling effects are alsomaximised; the use of gradient methods is generally impossible, as isthe use of pure polar solvents or mixtures with high polar solventcontents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts the separation on a type A support with a test solute of2,2,2-trifluoro-1-(9-anthryl)ethanol.

FIG. 1B depicts the separation on a type A support with a test solute ofindapamide.

FIG. 1C depicts the separation on a type A support with a test solute of2,2,2-trifluoro-1-(9-anthryl)ethanol.

FIG. 1D depicts the separation on a type A support with a test solute ofindapamide.

FIG. 1E depicts the separation on a type B support with a test solute ofoxazepam.

FIG. 2A depicts the separation on a type A support with a test solute ofindapamide.

FIG. 2B depicts the separation on a type A support with a test solute ofbenzoin.

FIG. 3A depicts the inversion exit order of enantiomers of an activepharmaceutical ingredient on a type A support eluted after 17454.

FIG. 3B depicts the inversion exit order of enantiomers of an activepharmaceutical ingredient on a type A support eluted before 17454.

METHODS OF THE INVENTION

The invention provides a method comprising the following successivesteps:

1) synthesis of at least one bifunctional alkenyloxyaryl oralkenylaryloxyaryl type compound with general formula[R—CH═CH—(X)—O]_(n)—Ar—Q,

where Q is a group which reacts with a hydrogen carried by a heteroatomselected from the group formed by oxygen, nitrogen and sulphur or aprecursor of such a group, and where:

n is in the range 1 to 20;

R is hydrogen or a linear or branched alkyl group or a linear orbranched alkoxy group or a hydroxyl or an aryl group, which may besubstituted;

X is a divalent linear alkyl group containing more than one carbon atomor a divalent branched alkyl group, or an aryl group, which may besubstituted with at least one group selected from the group formed byhydrogen, alkyl, alkoxy, hydroxyl or trihalogenoalkyl groups;

Ar is a divalent aryl or polyaryl group, optionally substituted with atleast one hydrogen atom or at least one group selected from the groupformed by alkyl, alkoxy, hydroxyl, trihalogenoalkyl, silyl, thiol,amino, aminoalkyl, amide, nitro, nitrosamino, N-amino, aldehyde, acid orester groups;

2) reacting at least one hydrogen of an alcohol, amine or thiol functionof at least one chiral unit of a product, preferably a glycosidic unitof a product selected from holosides, heteroholisides, oligosides,cyclooligosides, heterooligosides, polyosides, heteropolyosides, enzymesand proteins with at least one group Q of the bifunctional compound ofstep 1), to synthesise at least one chiral compound.

The compound selected from holosides, heteroholosides, oligosides,cyclooligosides, heterooligosides, polyosides, heteropolyosides, enzymesand proteins is generally selected from the following compounds:pullulan, beta-2,1-fructan (inulin), beta-1,4-mannane, cellulose,beta-1,3-glucan curdlan, chitosan, dextran, amylose-cyclodextrins,alpha-1,3-glucan, beta-1,2-glucan, and beta-1,4-xylan, the formula forwhich are given below.

Group Q is preferably selected from the group formed by the followinggroups: —N═C═O or a precursor thereof; —NH₂, —CON₃ or —COCl or aprecursor thereof; —COOH, —N═C═S, —CH₂—Y, where Y is Cl or Br or I ormethylsulphonyloxy or paratoluenesulphonyloxy or3,5-dimethylphenylsulphonyloxy.

The method of the invention may comprise a supplementary hydrosilylationstep, before or after step 2), to transform at least a portion of thealkenyl moieties R—CH═CH— using a silane (R₁, R₂, R₃)Si—H generally inthe presence of a metallic complex derived from platinum or rhodium to(R₁, R₂, R₃)—Si—CH(R)—CH₂— moieties, where:

R₁ is hydrogen or a methoxy or ethoxy group or a halogen or an amino oralkylamino group;

R₂ and R₃, which may be identical to or different from R₁, are alkoxy,hydroxyl, trihalogenoalkyl, linear or branched alkyl, or aryl groups;

R is hydrogen or a linear or branched alkyl group or a linear orbranched alkoxy group or a hydroxyl group or an aryl group which may besubstituted.

Hydrosilylation generally takes place in a solvent medium in thepresence of a suitable catalyst such as platinum.

where each Y (Y₁, Y₂ or Y₃) represents a sulphur or oxygen atom or thegroup NH;

each W (W₁, W₂ or W₃) represents an ethylenic radical with generalformula [R—CH═CH—(X)—O]_(n)—Ar—Z—

where Z represents a NH—CO group, or an —NH—CS group, or a CO group, ora CH₂ group;

and in which symbols R, X and Ar are defined below;

where n is a whole number in the range 5 to 2000;

and where each glycosidic unit contains at least 0.05 Y-W groups;

groups Y-W may be identical or different.

Polymerised and Cross Linked Clural Compounds

The invention particularly provides a polymerised and cross-linkedchiral compound or ester, amide, urea, carbamate, thioester orthiocarbamate derivatives of said polymerised and cross-linked chiralcompound, with general formula:

where:

q is at least 1 and less than 20;

s is at least 1 and less than 20000;

if r=0, the compound is a pure cross-linked chiral polymer, oligomer ormonomer;

if r≧1, the compound is a chiral polymer, oligomer or monomer which iscross-linked in a three-dimensional network and bonded to a cross-linkedsupport.

LINK A represents:

LINK B represents:

“chiral unit” represents a monomeric, oligomeric, cyclooligomeric orpolymeric chiral compound and optionally comprises a primary orsecondary amine function or a primary, secondary or tertiary hydroxylfunction or a sulphhydryl function and in which all or a portion ofthese functions have optionally been modified to the ester, amide, urea,carbamate, thioester or thiocarbamate;

Z represents a —CH₂— group or a —CO— group or a —NH—CO— group or a—NH—CS— group;

Y represents a sulphur or oxygen atom or the amino group;

n is in the range 1 to 20;

Ar represents a divalent aryl or polyaryl group;

X represents a divalent alkyl or aryl group;

R represents an alkyl group or hydrogen;

L represents a single bond or a bis-sulphhydryl or silane or an ethylenegroup which may be substituted or a disiloxane;

K represents a single bond or a siloxane or a silane;

“support” represents an organic or mineral support; functionalised by analkene or a hydrogenosilane or a sulphhydryl.

Thus the compound or one of its derivatives preferably has one of thefollowing formulae:

The method of the invention preferably comprises a supplementary stepfor treating at least a portion of the chiral compound obtained above toobtain a chiral support. The treatment is generally selected from thegroup formed by the three treatments described below.

A first treatment for the chiral compound consists of physicaldeposition of at least a portion of the compound on a support. Such atreatment generally consists of adding a co-solvent to the chiralcompound which is dissolved in a polar solvent in the presence of asupport, addition being followed by precipitation of the compound on thesupport, or evaporation of the chiral compound which is dissolved in apolar solvent in the presence of a support.

A second treatment for the chiral compound consists of physicaldeposition then grafting by covalently bonding at least part of thechiral compound onto a support, the support having been at leastpartially reacted with at least one group selected from the group formedby alkoxy, halogeno or aminosilane groups to form a derivative, thegroup also carrying a function of the type —SH, —SiH or —CH═CH—. Thesecond treatment generally comprises adding free alkenyl functions ofthe portion of the chiral compound to the derivative support followed byin situ cross-linking of the remaining alkenyl functions to constitute athree-dimensional chiral network. The reaction is generally carried outin a solvent with a high boiling point such as a hydrocarbon, toencourage the kinetics. The grafting reaction between at least a portionof the alkenyl functions of the chiral units (preferably glycosidic) ofthe chiral compound and at least a portion of the —SH, —SiH or —CH═CH—functions of the derivative support generally takes place in an organicsolvent in the presence of a suitable catalyst such as platinum salts orperoxides. When the chiral compound has undergone the supplementalhydrosilylation step, grafting is generally carried out on at least aportion of the hydrogen, alkoxy, halogeno or alkylaminosilane typeterminal groups.

Regarding the first and second treatments, the support is generallyselected from the group formed by gel type supports of native ormodified silica, oxides of zirconia, magnesium, aluminium, or titanium,glass beads, carbons or any organic polymer.

A third treatment for the chiral compound consists of at least partialpolymerisation, generally by cross-linking at least a portion of thechiral compound to obtain polymer beads which essentially constitute achiral support. One possible manner of carrying out the third treatmentgenerally comprises dissolving the portion of the chiral compound in asuitable solvent then reacting it in a two-phase medium, followed byevaporating the solvent to obtain a polymer in the form of beads orirregular particles, then polymerisation by intra- or inter-molecularcross-linking of at least a portion of the alkenyl moieties of theunits, preferably glycosidic, of that portion of the chiral compound, byheating in the presence of a polymerisation initiator such as aperoxide. A further manner of carrying out the third treatment comprisesthe same steps, with the exception of polymerisation by cross-linkingwhich is obtained by hydrosilylation, using hydrosilanes orhydrosiloxanes, of at least a portion of the alkenyl functions of thatportion of the chiral compound on bifunctional dithiol type compoundsHS—( . . . )—SH, dihydrogenosilanes HSi—( . . . )—SiH, or polyfunctionaltetramethyldisiloxane, or 1,3,5,7-tetramethylcyclo-tetrasiloxane, ormethylhydrocyclosiloxanes type compounds, or ethanediol type compoundsor with sulphur.

Polymerisation by cross-linking is known per se and has been described,for example, in J. Chromatogr. 1992, 594, 283-290. The techniquedescribed in this article can be used to prepare the chiral compounds ofthe invention. In general, the reaction is carried out in a solventwhich is inert towards hydrosilylation, such as toluene, 1,4-dioxane,chloroform, tetrahydrofuran (THE) or xylene, or mixtures of thesesolvents, at temperatures of 40° C. to 140° C. Using a catalyst such asmetallic platinum or rhodium complexes accelerates the reactionkinetics.

The hydrosilanes or hydrosiloxanes used to prepare the chiral compoundscan be defined by the following general formula:

R⁴: is an alkoxy, halogen or alkylamino group;

Ri: is identical to or different from R₁ and is an alkoxy, hydroxyl,aryl, halogen,

alkylamino, trihalogenoalkyl, or linear or branched alkyl group;

F: is (CH₂)_(u) or oxygen;

t: is 0 to 3000;

u: is 0 to 10.

When the chiral compound has undergone a supplemental hydrosilylationstep, polymerisation principally occurs by controlled hydrolysis of atleast a portion of the terminal hydrogenosilane, alkoxysilane,halogenosilane or N-alkylaminosilane type functions, which mainlyresults in substantially spherical particles of pure polymer.

The chiral support obtained above by one of the three treatments ispreferably used in accordance with the method of the invention in anoperation for separating chiral compounds or for preparing enantiomers.The operation is generally selected from the following methods: liquidchromatography, generally preparative or analytical liquidchromatography, comprising the following techniques: low, medium andhigh pressure (HPLC) liquid chromatography, counter-currentchromatography and simulated moving bed chromatography, gaschromatography, generally analytical or preparative, supercriticalchromatography, subcritical chromatography, centrifugal chromatography,electrophoresis, electrochromatography, or any membrane separationprocess, also asymmetrical synthesis.

Process for Synthesizing Polymers

The invention also provides a process for synthesising polymerscomprising the following successive steps:

1) synthesising at least one bifunctional alkenyloxyaryl oralkenylaryloxyaryl type compound with general formula[R—CH═CH—X—O]_(n)Ar—Q,

where Q is a group selected from the group formed by the followinggroups: —N═C═O or a precursor thereof, —NH₂ or —CON₃, —COCl or aprecursor thereof, —COOH, —N═C═S, —CH₂Y, where Y is Cl or Br or I ormethylsulphonyloxy or paratoluenesulphonyloxy or3,5-dimethylphenylsulphonyloxy, and where:

n is in the range 1 to 20;

R is hydrogen or a linear or branched alkyl group or a linear or abranched alkoxy group or a hydroxyl or an aryl group, which may besubstituted;

X is a linear or branched alkyl group or an aryl group, which may besubstituted with at least one group selected from the group formed byhydrogen, alkyl, alkoxy, hydroxyl and trihalogenoalkyl groups;

Ar is an aryl or polyaryl group, which may be substituted with at leastone hydrogen atom or a group selected from the group formed by alkyl,alkoxy, hydroxyl, trihalogenoalkyl, silyl, thiol, amino, aminoalkyl,amide, nitro, nitrosamino, N-amino, aldehyde, acid or ester groups;

2) polymerisation by the alkenyl moiety or by the R₁ group of thebifunctional compound of step 1), to synthesise at least one polymerfunctionalised by a group Q.

Bifunctional Compounds

The invention also provides any bifunctional alkenyloxyaryl oralkenylaryloxyaryl type compound with general formula[R—CH═CH—(X)—O]_(n)—Ar—Q,

where Q is a group which is reactive towards a hydrogen carried by aheteroatom selected from the group formed by oxygen, nitrogen andsulphur, or a precursor of such a group, and where:

n is in the range 1 to 20;

R is hydrogen or a linear or branched alkyl group or a linear orbranched alkoxy group or a hydroxyl or an aryl group, which may besubstituted;

X is an optional divalent linear or branched alkyl group or an arylgroup, which may be substituted with at least one group selected fromthe group formed by hydrogen, alkyl, alkoxy, hydroxyl andtrihalogenoalkyl groups;

Ar is a divalent aryl or polyaryl group, which may be substituted withat least one hydrogen atom or with at least one group selected from thegroup formed by alkyl, alkoxy, hydroxyl, trihalogenoalkyl, silyl, thiol,amino, aminoalkyl, amide, nitro, nitrosamino, N-amino, aldehyde, acid orester groups;

excluding the following compounds: 4-allyloxyaniline, 4-allyloxybenzoicacid, its acid chloride, and 4-allyloxyphenylisocyanate. The synthesisand/or use of these compounds is described in the following articles:

M. A. Apfel, H. Finkelmann, G. M. Janini, R. J. Laub, B. H. Lëhmann, A.Price, W. L. Roberts, T. J. Shaw and C. A. Smith, Analytical Chemistry,1985, 57, 651-658;

Y. Nambu and T. Endo, Journal of Organic Chemistry, 1993, 58, 1932-1934;

G. Yi, J. S. Bradhsaw, B. E Rossiter, S. L. Reese, R. Petersson, K. E.Markides and M. L. Lee, Journal of Organic Chemistry, 1993, 58,2561-2565;

G. Yi, J. S. Bradhsaw, N. E Rossiter, A. Malik, W. Li, H. Yun, M. L.Lee, Journal of Chromatography A, 673 (1994), 219-230;

G. Yi, J. S. Bradhsaw, B. E Rossiter, A. Malik, W. Li, H. Yun, M. L.Lee, Journal of Heterocyclic Chemistry, 352, 621 (1995);

G. Yi, W. Li, J. S. Bradhsaw, A. Malik, M. L. Lee, Journal ofHeterocyclic Chemistry, 32, 1715 (1995).

Group Q is preferably selected from the group formed by the followinggroups: —N═C═O or a precursor thereof, —NH₂ or —CON₃, —COCl or itsprecursor, —COOH, —N═C═S, —CH₂Y, where Y is Cl or Br or I ormethylsulphonyloxy or paratoluenesulphonyloxy or3,5-dimethylphenylsulphonyloxy.

Chiral Compounds

The invention also provides any chiral compound which can be obtained bya substitution reaction of at least one hydrogen of an alcohol, amine orthiol function of at least one chiral unit of a product, preferably aglycosidic unit of a product selected from holosides, heteroholosides,oligosides, cyclooligosides, heterooligosides, polyosides,heteropolyosides, enzymes and proteins, with at least one group Q of theabove bifunctional compound. The invention still further provides anychiral compound which can be obtained by hydrosilylation of thesubstituted chiral compound to transform at least a portion of thealkenyl moieties R—CH═CH— using a silane (R₁, R₂, R₃)Si—H generally inthe presence of a metallic complex derived from platinum or rhodium to(R₁, R₂, R₃)Si—CH(R)—CH₂— moieties, where:

R₁ is hydrogen or an alkoxy group or a halogen or an amino or alkylaminogroup;

R₂ and R₃, which may be identical to or different from R₁, are alkoxy,hydroxyl, trihalogenoalkyl, linear or branched alkyl or aryl groups;

R is hydrogen or a linear or branched alkyl group or a linear orbranched alkoxy group or a hydroxyl group or an aryl group which may besubstituted.

The invention yet still further provides any chiral compound which canbe obtained by hydrosilylation of a bifunctional compound to transformat least a portion, of the alkenyl moieties R—CH═CH— using a silane (R₁,R₂, R₃)Si—H generally in the presence of a metallic complex derived fromplatinum or rhodium to (R₁, R₂, R₃)Si—CH(R)—CH₂— moieties, where:

R₁ is hydrogen or an alkoxy group or a halogen or an amino or alkylaminogroup;

R₂ and R₃, which may be identical to or different from R₁, are alkoxy,hydroxyl, trihalogenoalkyl, linear or branched alkyl or aryl groups;

R is hydrogen or a linear or branched alkyl group or a linear orbranched alkoxy group or a hydroxyl group or an aryl group which may besubstituted;

then by reacting at least one hydrogen of an alcohol, amine or thiolfunction of at least one chiral unit of a product, preferably aglycosidic unit of a product selected from holosides, heteroholisides,oligosides, cyclooligosides, heterooligosides, polyosides,heteropolyosides, enzymes and proteins, with at least one group Q of theabove bifunctional compound.

Chiral Support

The invention also provides any chiral support which can be obtainedfrom the preceding chiral compounds by physical deposition on a support.The invention also provides any chiral support which can be obtainedfrom the above chiral compounds and a support, the support having beingderived from at least one group selected from the group formed byalkoxy, halogeno or aminosilane groups also comprising a —SH, —SiH or—CH═CH— type function, by forming covalent chemical bonds with at leasta portion of the alkenyl moieties of said chiral compounds followed byin situ cross-linking of the remaining alkenyl functions to constitute athree-dimensional chiral network.

More generally, the invention provides any chiral support comprising atleast one of the above chiral compounds and at least one support. Thecompound is preferably chemically bonded to the support, by at least onecovalent chemical bond.

The support is generally selected from the group formed by gel typesupports of native or modified silica, oxides of zirconia, magnesium,aluminium or titanium, glass beads, carbons or any organic polymer.

The invention also provides any chiral support which can be obtainedfrom at least one of the above chiral compounds by polymerisationgenerally by cross-linking at least a portion of the alkenyl moieties ofsaid chiral compound to obtain polymer beads.

More generally, the invention provides any chiral support comprisingbeads of at least one of the above chiral compounds.

Finally, the invention provides any process for separating chiralcompounds or for preparing enantiomers using at least one chiral supportas above in an operation selected from the following methods: liquidchromatography, gas chromatography, supercritical chromatography,subcritical chromatography, centrifugal chromatography, electrophoresis,electrochromatography, or any membrane separation process, alsoasymmetrical synthesis.

The following examples illustrate the invention without in any waylimiting its scope.

EXAMPLES 1. Preparation of Chromatographic Supports in Accordance withthe Invention

a) Preparation of Parapent-4-enoxybenzoic Acid:

2 g of sodium hydroxide, 15 ml of distilled water, 7.6 g of methyl4-hydroxybenzoate, 0.16 g of tetrabutylammonium bromide and 5.92 ml of5-bromopent-1-ene were successively placed in a reactor. Vigorousstirring was maintained overnight at ambient temperature. After adding30 ml of a 2.5 M sodium hydroxide solution, the reaction medium washeated to 60-80° C. for 90 minutes. It was then diluted with 120 ml ofdistilled water and extracted with two times 50 ml of diethyl ether. Theaqueous phase was acidified with 10 ml of concentrated hydrochloric acidto precipitate the acid. After filtering, washing with distilled waterand drying in a dessicator over P₂O₅, the acid was obtained in a yieldof 93%.

b) Preparation of the Acid Chloride of Parapent-4-enoxybenzoic Acid:

10.3 g of parapent-4-enoxybenzoic acid was suspended in 60 ml of tolueneto which 17 ml of thionyl chloride was added. The reaction mixture washeated under reflux for 30 minutes then vacuum evaporated. The oilyresidue obtained was vacuum distilled (110° C./1 mm of Hg). The yieldfrom this synthesis was 85%.

c) Preparation of Parapent-4-enoxybenzoylazide:

A solution of 11.27 g of parapent-4-enoxybenzoyl chloride dissolved in15 ml of acetone was added dropwise to an aqueous solution of sodiumnitride (3.9 g in 22 ml of distilled water) at ambient temperature withvigorous stirring. Following addition, the reaction medium was stirredfor one hour then diluted with 50 ml of water. After decanting, thecolourless oil obtained was dried over magnesium sulphate. (Yield=80%).

d) Preparation of Parapent-4-enoxyphenylisocyanate

11.6 g of parapent-4-enoxybenzoylazide was dissolved in 80 ml ofanhydrous toluene then heated under reflux for 90 min. The solvent wasthen vacuum evaporated and the residue which had the appearance of acolourless oil was vacuum distilled (100° C./1 mm of Hg). The yield fromthis synthesis was 94%.

a) Preparation of a Tris[3,6-(4-allyloxyphenyl)urethane]Cellulose (forPreparation of a type B support):

2.5 g of microcrystalline cellulose, 75 ml of pyridine and 38 ml ofheptane were placed in a reactor. Stirring and heating the reactionmixture dehydrated the cellulose by azeotropic entrainment. 9.31 g of4-allyloxyphenylisocyanate and 0.05 g of 4-dimethylaminopyridine wereadded to the mixture and it was heated under reflux for 8 hours. At theend of the reaction, 65 ml of methanol was added and refluxing wascontinued for 15 minutes. The cellulose derivative was then washed threetimes with 300 ml of distilled water then 140 ml of methanol.

b) Preparation of aTris[6-(4-allyloxyphenyl)urethane-2,3,6-(3,5-dimethyalhenyl)urethane]Cellulose(for the preparation of a type A support)

2.5 g of microcrystalline cellulose, 75 ml of pyridine and 38 ml ofheptane were placed in a reactor. Stirring and heating the reactionmixture dehydrated the cellulose by azeotropic entrainment. 1.35 g of4-allyloxyphenylisocyanate, 6.80 g of 3,5-dimethylphenylisocyanate and0.05 g of 4-dimethylaminopyridine were added to the mixture and it washeated under reflux for 8 hours. At the end of the reaction, 65 ml ofmethanol was added and refluxing was continued for 15 minutes. Thecellulose derivative was then washed three times with 300 ml ofdistilled water then 140 ml of methanol.

3. Composite Obtained Between a Cellulose Derivative and a ModifiedSilica (mercaptopropyl silica)

a) Preparation of a Mercaptopropyl Silica

10 g of Kromasil silica (5 μm, 100- where 1.0=0.1 nm) suspended in 50 mlof toluene was placed in a reactor. The medium was heated under refluxto dehydrate the silica by azeotropic entrainment. 45 ml ofmercaptopropyltrimethoxysilane and 20 ml of pyridine were then added.The reaction mixture was stirred and heated at 100° C. for two days.After filtering and washing with methanol and diethylether then vacuumdrying at 60° C., a mercaptopropyl silica was obtained with a degree ofgrafting of 0.85 mmol/g of thiol function.

b) Preparation of Composite

b1) For B type support: 0.45 g of tris[2,3,6-(4-allyloxyphenyl)urethane]cellulose was dissolved in 27 ml of tetrahydrofuran, then 3 g ofKromasil mercaptopropyl silica was added. After ultrasound degassing forthree minutes, it was evaporated to dryness. The composite formed wasfiltered, then dried in the open air.

B2) For an A type support: 0.45 g oftris[6-(4-allyloxyphenyl)urethane-2,3,6-(3,5-dimethylphenyl)urethane]cellulose was dissolved in 27 ml of tetrahydrofuran, then 3 g ofmercaptopropyl Kromasil silica was added. After ultrasound degassing forthree minutes, it was evaporated to dryness. The composite formed wasfiltered, then dried in the open air.

a) Preparation of a Type A Chromatographic Support:

The composite prepared as above (3-b2) was dissolved in 17 ml of heptanein the presence of a catalytic quantity of benzoyl peroxide. Thereaction medium was heated under reflux for 14 hours then filtered andair dried.

b) Preparation of a Type B Chromatographic Support:

The composite prepared as above (3-b1) was dissolved in 17 ml of heptanein the presence of a catalytic quantity of benzoyl peroxide. Thereaction medium was heated under reflux for 14 hours then filtered andair dried.

B—USE OF CHROMATOGRAPHIC SUPPORTS IN ACCORDANCE WITH THE INVENTIONIA—Example of Separation on a Type A Support Test solute:2,2,2-trifluoro-1-(9-anthryl)ethanol

Please refer to FIG. 1A

Mobile Phase: 100% Pure Chloroform

UV detection at 254 nm; O. D. (optical density)=0.2

Flow rate: 1 ml/min=P6.2 MPa (600 psi)°

T₀=2.95″ (non-retained solute transit time measured using1,3,5,tritert-butylbenzene)

Partition ratios: k′₁=1.03 k′₂=2.56

↑: t₀ injection

Relative retention ratio: α=2.64

IB—Example of Separation on a Type A Support Test Solute: Indapamide

Please refer to FIG. 1B

Mobile Phase: 100% Pure Chloroform

UV detection at 254 nm; O. D.=0.2

Flow rate: 1 ml/min P=6.2 MPa (600 psi)°

T₀=2.95′ (non-retained solute transit time measured using1,3,5,tritert-butylbenzene)

Partition ratios: k′₁=7.47 k′₂=9.17

↑: t₀ injection

Relative retention ratio: α=1.23

IC—Example of Separation on a Type A Support Test solute:2,2,2-trifluoro-1-(9-anthryl)ethanol

Please refer to FIG. 1C

Mobile Phase: 100% Pure Dichloromethane

UV detection at 254 nm; O. D.=0.2

Flow rate: 1 ml/min P=6.2 MPa (600 psi)°

T₀=2.95′ (non-retained solute transit time measured using1,3,5,tritert-butylbenzene)

Partition ratios: k′₁=0.56 k′₂=1.03

↑: t₀ injection

Relative retention ratio: α=1.85

ID—Example of Separation on a Type A Support Test Solute: Indapamide

Mobile Phase: 100% Pure Dichloromethane

UV detection at 254 nm; O. D.=0.2

Flow rate: 1 ml/min P=6.2 MPa (600 psi)°

T₀=2.95′ (non-retained solute transit time measured using1,3,5,tritert-butylbenzene)

Partition ratios: k′₁=2.13 k′₂=2.39

↑: t₀ injection

Relative retention ratio: α=1.12

IE—Example of Separation on a Type B Support Test Solute: Oxazepam

Please refer to FIG. 1E

Mobile Phase: 70/30/0.1 Heptane/isoyropanol/diethylamine

UV detection at 254 nm; O. D.=0.1

Flow rate: 1 ml/min P=5.5 MPa (800 psi)°

T₀=2.82′ (non-retained solute transit time measured using1,3,5,tritert-butylbenzene)

Partition ratios: k′₁=2.69 k′₂=10.18

↑t: t₀ injection

Relative retention ratio: α=3.78

IIA—Example of Separation on a Type A Support Test Solute: Indapamide

Please refer to FIG. 2A

Mobile Phase: Reverse Mode Elution Gradient Water (100%) to Acetonitrile(100%) in 60 Minutes

UV detection at 254 nm; O. D.=0.5

Flow rate: 1 ml/min

T₀=2.80′ (non-retained solute transit time measured using1,3,5,tritert-butylbenzene)

Partition ratios: k′₁=11.03 k′₂=11.58

↑: t₀ injection

Relative retention ratio: α=1.05

IIB—Example of Separation on a Type A Support Test Solute: Benzoin

Please refer to FIG. 2B

Mobile Phase: Normal Mode Elution Gradient Heptane (100%) to Isopropanol(100%) in 60 Minutes

20 UV detection at 254 nm; O. D.=0.02

Flow rate: 1 ml/min

T₀=2.90′ (non-retained solute transit time measured using1,3,5,tritert-butylbenzene)

Partition ratios: k′₁=5.10 k′₂=6.28

↑: t₀ injection

Relative retention ratio: α=1.23

III: Example of Inversion of Order of Exit of Enantiomers of an ActivePharmaceutical Ingredient on a Type A Support Active Ingredient(eutomer): 17454 Unwanted Enantiomer (distomer): 17455

CONDITIONS 2: 17455 Eluted before 17454

Mobile Phase:

heptane + 2% diethylamine 10% dichloromethane 22% heptane 66% methanol 2% Retention time of S 17455: 13.86' Retention time of S 17454: 14.93'(see diagram below)

Other parameters for conditions 1 and conditions 2 were identical,namely:

detection wavelength: 270 nm, UV

flow rate: 1 ml/min

20 μl volume injected, i.e., 20 μg of solute at the concentration used.

III continued CONDITIONS 1

Please refer to FIG. 3A and 3B

The foregoing examples can be repeated with analogous results bysubstituting the reactants and/or the general or particular conditionsdescribed in the invention for those used in the examples.

In the light of the above description, the skilled person can readilydetermine the essential characteristics of the invention and could makevarious changes and modifications without departing from the spirit andscope of the invention, to adapt it to various uses and conditions forcarrying out the invention.

What is claimed is:
 1. A chiral compound obtained by reaction of atleast one hydrogen of an alcohol, amine, or thiol function of at leastone chiral unit of a product with at least one group Q of a bifunctionalalkenoxyaryl or alkenylaryloxyaryl type compound with formula(R—CH═CH—(X)—O)_(n)—Ar—Q, where Q is —N═C═O or a precursor thereof;—NH₂or —CON₃; —COCl or its precursor; —COOH; —N═C═S; or —CH₂Y, where Yis Cl or Br or I or methylsulphonyloxy or paratoluenesulphonyloxy or3,5-dimethylphenylsulphonyloxy and where: n is in the range 1 to 20; Ris hydrogen or a linear or branched alkyl group or a linear or branchedalkoxy group or hydroxyl or an aryl group, optionally substituted; X isa linear alkyl group carrying more than one carbon atom or a branchedalkyl group, or an aryl group, optionally substituted with at least onegroup selected from the group consisting of hydrogen, alkyl, alkoxy,hydroxyl and trihalogenoalkyl groups; and Ar is an aryl or polyarylgroup, optionally substituted with at least one hydrogen atom or with atleast one group selected from the group consisting of alkyl, alkoxy,hydroxyl, trihalogenoalkyl, silyl, thiol, amino, aminoalkyl, amide,nitro, nitrosamino, N-amino, aldehyde, acid and ester groups, excludingthe following compounds: 4-allyloxyaniline, 4-allyloxybenzoic acid, itsacid chloride, and 4-allyloxyphenylisocyanate.
 2. A chiral compoundwhich can be obtained by hydrosilylation of the chiral compound of claim1 to transform at least a portion of the alkenyl moieties R—CH═CH— usinga silane (R₁, R₂, R₃)Si—H generally in the presence of a metalliccomplex derived from platinum or rhodium to (R₁, R₂, R₃)—Si—CH(R)—CH₂—moieties, where: R₁ is hydrogen or an alkoxy group or a halogen or anamino or alkylamino group; R₂ and R₃, which may be identical to ordifferent from R₁, are alkoxy, hydroxyl, trihalogenoalkyl, linear orbranched alkyl or aryl groups; R is hydrogen or a linear or branchedalkyl group or a linear or branched alkoxy group or a hydroxyl group oran aryl group optionally substituted.
 3. A chiral compound which can beobtained by hydrosilylation of the bifunctional alkenyloxyaryl oralkenylaryloxyaryl type compound with formula (R—CH═CH—(X)—O)_(n)—Ar—Q,where Q is —N═C═O or a precursor thereof: —NH₂ or —CON₃; —COCl or itsprecursor; —COOH; —N═C═S; or —CH₂Y, where Y is Cl or Br or I ormethylsulphonyloxy or paratoluenesulphonyloxy or3,5-dimethylphenylsulphonyloxy and where: n is in the range 1 to 20; Ris hydrogen or a linear or branched alkyl group or a linear or branchedalkoxy group or hydroxyl or an aryl group, optionally substituted; X isa linear alkyl group carrying more than one carbon atom or a branchedalkyl group, or an aryl group, optionally substituted with at least onegroup selected from the group consisting of hydrogen, alkyl, alkoxy,hydroxyl and trihalogenoalkyl groups; and Ar is an aryl or polyarylgroup, optionally substituted with at least one hydrogen atom or with atleast one group selected from the group consisting of alkyl, alkoxy,hydroxyl, trihalogenoalkyl, silyl, thiol, amino, aminoalkyl, amide,nitro, nitrosamino, N-amino, aldehyde, acid and ester groups, excludingthe following compounds: 4-allyloxyaniline, 4-allyloxybenzoic acid, itsacid chloride, and 4-allyloxyphenylisocyanate to transform at least aportion of alkenyl moieties R—CH+CH— using a silane (R₁, R₂, R₃)—Si—H inthe presence of a metallic complex derived from platinum or rhodium to(R₁, R₂, R₃)—Si—CH(R)—CH₂— moieties, where: R₁ is hydrogen or an alkoxygroup or a halogen or an amino or alkylamion group; R₂ and R₃, which maybe identical to or different from R₁, are alkoxy, hydroxyl,trihalogenoalkyl, linear or branched alkyl or aryl groups; then byreacting at least one hydrogen of an alcohol, amine or thiol function ofat least one chiral unit of a product with at least one group Q of thehydrosilylated bifunctional alkenyloxyaryl or alkenylaryloxyaryl typecompound.
 4. A chiral compound according to claim 1, in which saidchiral unit of a product is a glycosidic unit of a product selected fromholosides, heterobolosides, oligosides, cyclooligosides,heterooligosides, polyosides, heteropolyosides, enzymes and proteins. 5.A chiral compound according to claim 2, wherein the bifunctionalcompound is parapent-4-enoxybenzoic acid.
 6. A chiral compound accordingto claim 1, wherein the bifunctional compound is selected from the groupconsisting of parapent-4-enoxybenzoic acid, the acid chloride thereof,parapent-4-enoxybenzoylazide, and parapent-4-enoxyphenylisocyanate.
 7. Achiral compound according to claim 5, wherein the bifunctional compoundis parapent-4-enoxybenzoic acid.
 8. A chiral compound according to claim1, wherein the bifunctional compound is parapent-4-enoxybenzoic acid. 9.A chiral compound according to claim 4, wherein the bifunctionalcompound is parapent-4-enoxybenzoic acid.
 10. A chiral compoundaccording to claim 2, in which said chiral unit of a product is aglycosidic unit of a product selected from holosides, heteroholosides,oligosides, cyclooligosides, heterooligosides, polyosides,heteropolyosides, enzymes and proteins.
 11. A chiral compound accordingto claim 3, in which said chiral unit of a product is a glycosidic unitof a product selected from holosides, heteroholosides, oligosides,cyclooligosides, heterooligosides, polyosides, heteropolyosides, enzymesand proteins.
 12. A chiral compound obtained by hydrosilylation ofanother chiral compound obtained by reaction of at least one hydrogen ofan alcohol, amine, or thiol function of at least one chiral unit of aproduct with at least one group Q of a bifunctional compound wherein thebifunctional compound is an alkenyloxyaryl or alkenylaryloxyaryl typecompound with formula (R—CH═CH—(X)—O)_(n)—Ar—Q, where Q is —N═C═O or aprecursor thereof; —NH₂ or —CON₃; —COCl or its precursor; —COOH; —N═C═S;or —CH₂Y, where Y is Cl or Br or I or methylsulphonyloxy orparatoluenesulphonyloxy or 3,5-dimethylphenylsulphonyloxy and where: nis in the range 1 to 20; R is hydrogen or a linear or branched alkylgroup or a linear or branched alkoxy group or hydroxyl or an aryl group,optionally substituted; X is a linear alkyl group carrying more than onecarbon atom or a branched alkyl group, or an aryl group, optionallysubstituted with at least one group selected from the group consistingof hydrogen, alkyl, alkoxy, hydroxyl and trihalogenoalkyl groups; and Aris an aryl or polyaryl group, optionally substituted with at least onehydrogen atom or with at least one group selected from the groupconsisting of alkyl, alkoxy, hydroxyl, trihalogenoalkyl, silyl, thiol,amino, aminoalkyl, amide, nitro, nitrosamino, N-amino, aldehyde, acidand ester groups, excluding the following compounds: 4-allyloxyaniline,4-allyloxybenzoic acid, its acid chloride, and4-allyloxyphenylisocyanate; wherein, the reaction transforms at least aportion of the alkenyl moieties R—CH═CH— using a silane (R₁, R₂,R₃)—Si—H in the presence of a metallic complex derived from platinum orrhodium to (R₁, R₂, R₃)—Si—CH(R)—CH₂— moieties, where: R₁ is hydrogen oran alkoxy group or a halogen or an amino or alkylamino group; R₂ and R₃,which may be identical to or different from R₁, are alkoxy, hydroxyl,trihalogenoalkyl, linear or branched alkyl or aryl groups; and R ishydrogen or a linear or branched alkyl group or a linear or branchedalkoxy group or a hydroxyl group or an aryl group optionallysubstituted.
 13. The chiral compound according to claim 12 in which saidchiral unit of a product is a glycosidic unit of a product selected fromholosides, heteroholosides, oligosides, cyclooligosides,heterooligosides, polyosides, heteropolyosides, enzymes and proteins.14. The chiral compound according to claim 12 wherein the bifunctionalcompound is selected from the group consisting ofparapent-4-enoxybenzoic acid, the acid chloride thereof,parapent-4-enoxybenzoylazide, and parapent-4-enoxyphenylisocyanate. 15.The chiral compound according to claim 12, wherein the bifunctionalcompound is parapent-4-enoxybenzoic acid.
 16. The chiral compoundaccording to claim 13, wherein the bifunctional compound isparapent-4-enoxybenzoic acid.
 17. The chiral compound according to claim14, in which said chiral unit of a product is a glycosidic unit of aproduct selected from holosides, heteroholosides, oligosides,cyclooligosides, heterooligosides, polyosides, heteropolyosides, enzymesand proteins.
 18. A compound according to claim 10, wherein thebifunctional compound is parapent-4-enoxybenzoic acid.
 19. The chiralcompound according to claim 6, in which said chiral unit of a product isa glycosidic unit of a product selected from holosides, heteroholosides,oligosides, cyclooligosides, heterooligosides, polyosides,heteropolyosides, enzymes and proteins.
 20. The chiral compoundaccording to claim 3, wherein the bifunctional compound is selected fromthe group consisting of parapent-4-enoxybenzoic acid, the acid chloridethereof, parapent-4-enoxybenzoylazide, andparapent-4-enoxyphenylisocyanate.
 21. The chiral compound according toclaim 11, wherein the bifunctional compound is parapent-4-enoxybenzoicacid.
 22. The chiral compound according to claim 20, in which saidchiral unit of a product is a glycosidic unit of a product selected fromholosides, heteroholosides, oligosides, cyclooligosides,heterooligosides, polyosides, heteropolyosides, enzymes and proteins.23. The chiral compound according to claim 2 wherein the bifunctionalcompound is selected from the group consisting ofparapent-4-enoxybenzoic acid, the acid chloride thereof,parapent-4-enoxybenzoylazide, and parapent-4-enoxyphenylisocyanate. 24.The chiral compound according to claim 23, in which said chiral unit ofa product is a glycosidic unit of a product selected from holosides,heteroholosides, oligosides, cyclooligosides, heterooligosides,polyosides, heteropolyosides, enzymes and proteins.